1. Field of the Invention
The invention relates to new platinum(IV) coordination complexes with alkyl amides and preparation of them from potassium tetrachloroplatinate(II) and dialkylacetamides by way of oxidative addition under mild reaction conditions. The product of the reaction starting with dimethylacetamide as an amide ligand was used in a new route for the preparation of a complicated aromatic N-substituted acetamide, an important intermediate in the preparation of antihistamines (diphenhydramine hydrochloride).
2. Prior Art and Objectives
The importance of coordination compounds and organometallic compounds has increased substantially in recent years with the proliferation of uses of these compounds as catalysts and therapeutic agents. Many of the chemical processes in which coordination compounds are employed are truly catalytic; that is, they are accelerated by very small quantities of the compound which can be recovered virtually unchanged after completion of the reaction. On the other hand, metal complexes are employed in reactions where they serve as starting materials for compounds that cannot otherwise be readily produced, changed in the process, or are not a constituent of the product, so that the metal can be recovered after completion of the reaction. In metal complexes employed as therapeutic agents, a high degree of specificity exists, but as a result of the high level of interest in this field, those highly skilled can determine the biochemical efficacy of a compound from its composition, structure, and physical properties.
To appreciate the means whereby the composition and structure of the complex can be varied within the general framework, a review of the basic structure is useful. Coordinating or complexing Lewis bases (electron pair donors) called ligands react with metals (usually heavy metals) or metal ions. The geometric configuration of the complex depends upon the nature of the ligand, including the total number of atoms and the number of donor atoms on each ligand. The position of a ligand with respect to its attachment to the central atom (i.e., cis or trans) may be varied. This can affect the complex's stability and functionality in chemical and therapeutic applications. Coordination compounds are often categorized in terms of the rate in which they undergo substitution or loss of ligands.
Notwithstanding its high cost as a scarce precious metal, complexes of platinum are extensively used chemically and therapeutically. In the latter use, the anticancer properties of cis-dichlorodiammine platinum(II) (cis-Pta.sub.2 Cl.sub.2) are well known. This heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammine ligands (in the cis position with a square-planar configuration) is widely used in human cancer chemotherapy. Many variations from this structure and composition have been synthesized and evaluated in an effort to understand the mechanism of action and to develop a cure for the disease.
Practitioners, by selection from a variety of ligands for platinum complexes, have synthesized and evaluated many compounds for efficacy as anticancer agents. In the literature, B. Rosenberg, Naturwissenschaften 60, 399, (1973), summarized the relationship of structure and activity for platinum compounds. From this summary, certain generalizations can be drawn:
active compounds exchange only some of their ligands quickly (chloride is fast; ammine is slow);
a "window of lability" exists for the leaving ligand (i.e., bracketed between nitrate which is too fast and thiocyanate which is too slow);
active complexes are neutral;
active molecules are of square planar or octahedral geometric structure;
active complexes have two cis leaving groups or one bidentate leaving group; and
ligands trans to the leaving group should be strongly bonded.
With these generalities as guidelines, those skilled in the art, with a reasonable degree of certainty, can predict the efficacy of a therapeutic compound. It would be of interest to see if similar guidelines apply to chemical applications.
While a great variety of coordination compounds is possible by choice of ligands, in view of its therapeutic use, much interest is centered on cis-Pta.sub.2 Cl.sub.2 with its ammine ligands. Analogs with ammonia-derived organic ligands could be valuable, chemically as a carrier of the labile nitrogen-containing radical for synthesis of difficultly prepared compositions, as well as biochemically through the relationship of the nitrogen-containing radical of amino acid constituents of animal tissue. This latter may help elucidate the selective destruction of cancerous cells by platinum compounds.
In U.S. Pat. No. 4,283,342, issued Aug. 11, 1981, Yolles obtained platinum coordination compounds of quinones by reactions of cis-dichloro platinum(II) in substituted amide solvents.
Accordingly, it is an object of the present invention to prepare novel platinum complexes having nitrogen-containing organic ligands.
It is a further object of the present invention to prepare a platinum complex with amide ligands.
It is yet another objective of the present invention to prepare a difficultly synthesized aromatic derivative of acetamides (N-2-phenylethyl(methyl)acetamide), and the preparation of a class of antihistamines by employing platinum complexes containing amide ligands and benzyl bromide.